PL188649B1 - Compositions for once-a-day administration for use in treating diseases involving mediator effect of cyclooxygenase-2 - Google Patents

Abstract

This invention is directed to a pharmaceutical composition for the treatment of cyclooxygenase-2 mediated diseases, said composition being suitable for once a day administration, said composition comprising a cyclooxygenase-2 inhibiting compound characterized by high potency, a long half-life and a high degree of specificity for inhibiting cyclooxygenase-2 in preference to cyclooxygenase-1. Such a compound is exemplified 3-phenyl-4-(4-methylsulfonyl)phenyl)-2-(5H)-furanone. In one aspect, this invention is directed to a pharmaceutical composition for the treatment of cyclooxygenase-2 mediated diseases, said composition being suitable for once a day oral administration, said composition comprising 5 to 125 mgs of the above mentioned compound. The invention is also directed to a method of treating cyclooxygenase-2 mediated diseases comprising the once a day oral administration of 5 to 125 mgs of the above-mentioned compound. The invention is also directed to the use of the above-mentioned compound in the manufacture of a medicament containing 5 to 125 mgs of said compound for once a day administration for the treatment of cyclooxygenase-2 mediated diseases.

Description

The present invention therefore relates to a pharmaceutical composition for the treatment of cyclooxygenase-2 mediated diseases, comprising 3-phenyl-4- (4- (methylsulfonyl) phenyl) -2 (5H) -furanone as an active ingredient and pharmaceutically acceptable inactive ingredients. wherein said composition is in the form of a unit dosage form for once-a-day oral administration containing 12.5 mg of 3-phenyl-4- (4- (methylsulfonyl) phenyl) -2 (5H) furanone, in combination with pharmaceutically acceptable excipients.

The invention also relates to the use of 3-phenyl-4- (4- (methylsulfonyl) phenyl) -2 (5H) -furanone for the manufacture of a once-daily oral dosage unit form containing 12.5 mg, 25 mg or 50 mg. 3-phenyl-4- (4- (methylsulfonyl) phenyl) -2 (5H) -furanone, for the treatment of an inflammatory disease responsive to treatment with a non-steroidal anti-inflammatory drug.

In one embodiment, the disease is pain following surgery and dental procedures.

In another embodiment, the disease is osteoarthritis.

In another embodiment, the disease is rheumatoid arthritis.

In yet another embodiment, the disease is pain following surgery and dental procedures.

As stated, pharmaceutical compositions as defined above for the treatment of the aforementioned COX-2 mediated diseases may optionally contain one or more ingredients enumerated above.

In one embodiment, the composition of the invention comprises as inactive ingredients:

(a) microcrystalline cellulose, (b) lactose monohydrate, (c) hydroxypropyl cellulose, (d) croscarmellose sodium, (e) iron oxide, and (f) magnesium stearate;

In another embodiment, the composition of the invention comprises as inactive ingredients:

(a) microcrystalline cellulose, (b) anhydrous lactose,

188 649 (c) croscarmellose sodium and (d) magnesium stearate;

In another embodiment, the composition of the invention further comprises polyethylene oxide 400.

In another embodiment, the composition of the invention comprises as inactive ingredients:

(a) a sorbitol solution, (b) polyvinylpyrrolidone, (c) polyoxyethylene sorbitan monolaurate and (d) benzoic acid.

Pharmaceutical compositions containing the above-mentioned active ingredient may be in a form suitable for oral use, e.g. in the form of tablets, lozenges, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules, or syrups and elixirs. These compositions are intended for oral use and can be prepared according to known methods used in pharmaceutical production technology. They may contain one or more agents selected from the group consisting of sweetening agents, flavoring agents, coloring agents and preserving agents, to give them an elegant appearance and a pleasant taste. Tablets contain the active ingredient in admixture with non-toxic pharmaceutically acceptable excipients which are suitable for the manufacture of tablets. Such auxiliary agents can be, for example, inert diluents, such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate, granulating and disintegrating agents, e.g. corn starch or alginic acid, binders, e.g. starch, gelatin or gum. acacia and lubricants, e.g. magnesium stearate, stearic acid or talc.

Other suitable pharmaceutical forms are described in U.S. Patent No. 5,474,995. However, due to the unique property set of 3-phenyl-4- (4- (methylsulfonyl) -phenyl) -2 (5H) -furanone, including a long half-life , low solubility, high potency, minimized adverse effects on the digestive system (GI), we found the following oral forms particularly valuable:

Rapidisc® - Due to the above-described properties, 3-phenyl-4 - [(4-methylsulfonyl) phenyl] - (5H) -furanon-2 is especially suitable for sublingual, fast dissolving preparations. For example, due to the fact that it has no side effects on the gastrointestinal tract, it does not need to be taken with a lot of water. Suitable Rapidisc® pharmaceutical forms and methods for their preparation are disclosed in US Patent Nos. 4,305,502, 4,371,516, 4,470,202, 4,758,598, US 4,754,597, 5,046,618, and 5,188,882, incorporated herein by reference.

As stated above, it was found that 3-phenyl-4- (4- (methylsulfonyl) -phenyl) -2 (5H) furanone had an unexpected combination of properties. These active agents are not only potent, safe and effective at low daily oral doses of the active ingredient, but also have a half-life in humans long enough that a single oral dose of 12.5, 25 or 50 mg of the active ingredient once a day will provide effective and safe anti-inflammatory treatment throughout the 24-hour period. The agent is particularly useful in the treatment of chronic conditions such as rheumatoid arthritis, osteoarthritis, and Alzheimer's disease.

Example 1 Composition of a tablet produced by wet granulation.

Quantity in a tablet Ingredient 25.0 mg COX-2 inhibitor 79.7 mg Microcrystalline cellulose 79.7 mg Lactose monohydrate 6.0 mg Hydroxypropyl cellulose 8.0 mg Croscarmellose sodium 0.6 mg Iron oxide 1.0 mg Magnesium stearate

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The content of the active ingredient in the tablet may be adjusted to 12.5 mg or 450 mg by changing the total weight of the tablet and the ratio of the first three ingredients. In general, it is preferred to maintain a 1: 1 ratio of microcrystalline cellulose to lactose monohydrate.

Example Ia. The composition of the tablet produced by the wet granulation method

Quantity in a tablet Ingredient 12.5 mg COX-2 inhibitor 86.0 mg Microcrystalline cellulose 86.0 mg Lactose monohydrate 6.0 mg Hydroxypropyl cellulose 8.0 mg Croscarmellose sodium 0.6 mg Iron oxide 1.0 mg Magnesium stearate

Example Ib. The composition of the tablet produced by the wet granulation method

Quantity in a tablet Ingredient 10.0 mg COX-2 inhibitor 87.2 mg Microcrystalline cellulose 87.2 mg Lactose monohydrate 6.0 mg Hydroxypropyl cellulose 8.0 mg Croscarmellose sodium 0.6 mg Iron oxide 1.0 mg Magnesium stearate

Example II. The composition of the tablet produced by direct compression

Quantity in a tablet Ingredient 25.0 mg COX-2 inhibitor 106.9 mg Microcrystalline cellulose 106.9 mg Anhydrous lactose 7.5 mg Croscarmellose sodium 3.7 mg Magnesium stearate

The content of the active ingredient in the tablet may be adjusted from 12.5 mg or 50 mg by varying the total weight of the tablet and the ratio of the first three ingredients. It is generally preferred to maintain a 1: 1 ratio of microcrystalline cellulose to anhydrous lactose.

Example IIa. The composition of the tablet produced by direct compression

Quantity in a tablet Ingredient 12.5 mg COX-2 inhibitor 113.2 mg Microcrystalline cellulose 113.2 mg Anhydrous lactose 7.5 mg Croscarmellose sodium 3.7 mg Magnesium stearate

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Example III. Composition of a hard gelatin capsule

Quantity in a tablet Ingredient 25.0 mg COX-2 inhibitor 37.0 mg Microcrystalline cellulose 37.0 mg Anhydrous lactose 1.0 mg Magnesium stearate 1 capsule Hard gelatin capsule

The content of the active ingredient in the capsule can be adjusted to 12.5 mg or 50 mg by varying the total weight of the fill and the ratio of the first three ingredients. It is generally preferred to maintain a 1: 1 ratio of microcrystalline cellulose to anhydrous lactose.

Example IV. Oral solution

Quantity in a dose of 5 ml Ingredient 50.0 mg COX-2 inhibitor up to 5 ml Polyethylene oxide 400

The content of the active ingredient in a dose of 12.5 mg / 5 ml or 25 mg / 5 ml solution may be adjusted by varying the proportions of the above two components.

Example 5 Oral Suspension

Quantity in a dose of 5 ml Ingredient 101.0 mg COX-2 inhibitor 150.0 mg Polyvinylpyrrolidone 2.5 mg Polyoxy '(^ iy ^ l (^ nc ^ - ^! ^ (^ I ^ bii ^ anu) monolaurate 10.0 mg Benzoic acid up to 5 ml 1 capsule 70% sorbitol solution

The content of the active ingredient in the dose of the suspension may be adjusted to 12.5 mg / 5 ml, 25 mg / 5 ml or 50 mg / 5 ml by varying the ratio of the first two components.

Starting substances

Preparative Example 3-Phenyl-4- (4- (methylsulfonyl) phenyl) -2 (5H) furanone.

Step 1: 2-Bromo-1 - [(4-methylsulfonyl) phenyl] ethanone

A solution of 197 g of 4- (methylthio) acetophenone (described in J. Am. Chem. Soc., 1952, 74, p. 5475) in 700 ml of methanol and 3500 ml of CH2O2 was added over 30 minutes to 881 g of MMPP. After three hours at room temperature, the reaction mixture was filtered, the filtrate was washed with 2 liters of saturated aqueous NaHCO 3 solution and 1 liter of brine. The aqueous phase was extracted with 2 liters of CTECE. The combined extracts were dried over Na2SO4 and concentrated. 240 g of 4- (methylsulfonyl) -acetophenone were obtained in the form of a white solid.

To a solution of 174 g 4- (methylsulfonyl) acetophenone in 2.5 liters of CHCl, cooled to -5 ° C, was added 20 mg of AlCl2, followed by a solution of 40 ml of Br2 in 300 ml of CHClb. Then 1.5 liters of water was added to the reaction mixture, and the chloroform layer was separated. The aqueous layer was extracted with a liter of ethyl acetate. The combined organic extracts were dried over Na2SO4 and concentrated. The crude product was recrystallized from ethyl acetate, hexane (50:50), yielding 210 g of the title compound as a white solid.

Step 2: 3-Phenyl-4- (4- (methylsulfonyl) phenyl) -2 (5H) -furanone.

To a solution of 27.4 g (201 mmol) of phenylacetic acid and 60 g (216 mmol, 1.075 eq.) Of 2-bromo-1 - [(4-methylsulfonyl) phenyl] -ethanone from step 1 in 630 ml of acetonitrile, kept at 25 ° C, 30.8 mL (1.1 eq) of triethylamine was added slowly. The mixture was stirred for 20 minutes at room temperature and then stirred

188,649 was cooled in an ice bath. 60.1 ml (3 equivalents) of DBU was slowly added. After stirring for 20 minutes in an ice bath, the reaction was complete. The mixture was acidified with a 1N HCl solution (color change from dark brown to yellow). Then 2.4 liters of ice water was added, the mixture was stirred for a few minutes, the precipitate was filtered off and washed with water. 64 g of crude, wet product were obtained. This precipitate was dissolved in 750 ml of OHCl ™, dried over MgSO 4, filtered and 300 g of silica gel was added to the filtrate. The solvent was evaporated to almost dry (the silica gel was somewhat sticky), the residue was put on top of a cylindrical silica gel layer in a sintered glass funnel and eluted with 10% ethyl acetate in methylene chloride. After evaporating the solvent and switching to ethyl acetate, it was obtained

36.6 g (58%) of the title compound.

Analysis: Calculated for the formula C17H14O4S: C 64.95, H 4.49, S 10.20, Found: C 64.63 H 4.65, S 10.44%.

Preparative example 2

3-Phenyl-4- (4- (methylsulfonyl) phenyl) -2 (5H) -furanone

To a 20 ml glass ampoule, 1 g of 2 - [(4-methylsulfonyl) phenyl] phenylacetylene (J. Am. Chem. Soc. 1971, 93, p. 2979), 20 mg of Rhi4 (CO) i2, 1.5 g of of triethylamine, 10 ml of tetrahydrofuran and 1 ml of water, and the ampoule was placed in a 100 ml stainless steel autoclave. CO was passed through the reaction system three times, then CO was charged to 100 atmospheres at room temperature. The reaction was carried out at 100 ° C for 5 hours. The solution was then diluted with 50 ml of benzene and washed with brine and 1N HCl. The benzene solution was dried over Na2SO4 and concentrated. The crude products were separated by column chromatography on silica gel, eluting with ethyl acetate-hexane (2: 1). The title compound and its regioisomer were obtained.

Preparative example 3

3-Phenyl-4 - [(4-methylsulfbnyl) phenyl] - (5H) -furanon-2

Step 1: 2-Trimethylsilyloxy-4 - [(4-methylthio) phenyl] -3,4-dihydrofuran

To a solution of 3.86 g (19 mmol) of 4-bromothioanisole in 90 ml of diethyl ether kept at -78 ° C, 22 ml of a 1.7 M solution of tert-butyllithium in pentane (38 mmol) were added dropwise. The reaction mixture was stirred for 15 minutes at -78 ° C, 3.8 g of CuI was added and the reaction mixture was allowed to warm to -40 ° C over a period of 30 minutes. A solution of 1.7 g (5H) -) uranon-2 in 10 ml THF was added. After stirring for 1 hour, 2 ml of freshly distilled TMSCl was added dropwise, and the mixture was treated with ml of triethylamine and 50 ml of saturated NaHCOU solution, followed by extraction with diethyl ether (100 ml). The ether layer was dried over Na2SO4 and concentrated to give the crude title compound which was used for the next step without further purification.

Step 2: 4- (4- (Methylthio) phenyl) -2 (5H) -furanone

To a solution of 4 g Pd (OAc) 2 in 100 ml of acetonitrile, 5 g of the crude product from step 1 was added dropwise under nitrogen at room temperature. After 10 hours at room temperature, the mixture was concentrated under reduced pressure and the residue was purified by flash chromatography on silica gel, eluting with hexane-ethyl acetate (2: 1). The title compound was obtained.

Stage 3: 3-Iodo-4- (4- (methylthio) phenyl) -2 (5H1 - uranone

8.7 g of J2 was added to a solution of 3 g of the product of step 2 in 30 ml of pyridine. The mixture was stirred for 24 hours, diluted with diethyl ether (200 ml), washed with 100 ml of 5N HCl solution and 50 ml of 5N Na2S2O3. The ether layer was dried over Na2SO4 and concentrated to give the crude title compound.

Step 4: 3-Phenyl-4- (4- (metithothio) lenyl) -2 (5H) -furanone

A mixture of 4 g of the product from step 3.3.7 g of PhB (OH) 2, 0.4 g of PhsAs. 0.4 g PdCl2 (PhCN) 2 in 100 ml benzene and 15 ml 2N NaOH solution was boiled for

188,649 hours. After cooling to room temperature, 200 ml of diethyl ether were added and the reaction mixture was washed with 100 ml of saturated NaHCO3 solution. The organic layer was dried over MgSO4 and concentrated. The residue was purified by flash silica gel chromatography eluting with hexane-ethyl acetate (4: 1). The title compound was obtained.

Step 5: 3-Phenyl-4- (4- (methylsulfonyl) phenyl) -2 (5H) -furanone

5.5 g of MMPP was added to a solution of 3 g of the product of step 4 in 80 ml of a CIECE / methanol mixture (10: 1). The reaction mixture was stirred at room temperature for 2 hours, then it was diluted with 100 ml of hexane-ethyl acetate (1: 1). After filtration and concentration, the residue was purified by flash chromatography, eluting with ethyl acetate-hexane (2: 1). The title product was obtained.

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Claims (10)

Patent claims A pharmaceutical composition for the treatment of cyclooxygenase-2 mediated diseases comprising 3-phenyl-4- (4- (methylsulfonyl) phenyl-2 (5H) -furanone as an active ingredient and pharmaceutically acceptable inactive ingredients, characterized by that the composition is in the form of a unit dosage form for oral administration once daily containing 12.5 mg of 3-phenyl-4- (4- (methylsulfonyl) phenyl) -2 (5H) -furanone, in combination with pharmaceutically acceptable inactive ingredients 2. A composition according to claim 1 Claim 1, characterized in that it contains as inactive ingredients: (a) microcrystalline cellulose, (b) lactose monohydrate, (c) hydroxypropyl cellulose, (d) croscarmellose sodium, (e) iron oxide, and (f) magnesium stearate; or: (a) microcrystalline cellulose, (b) anhydrous lactose, (c) croscarmellose sodium, and (d) magnesium stearate; or in addition it contains: polyethylene oxide 400; or: (a) a sorbitol solution, (b) polyvinylpyrrolidone, (c) polyoxyethylene sorbitan monolaurate and (d) benzoic acid. 3. The use of 3-phenyl-4- (4- (methylsulfonyl) phenyl) -2 (5H) -furanone in the manufacture of a once-a-day oral dosage unit form containing 12.5 mg, 25 mg or 50 mg of 3-phenyl-4- (4- (methylsulfonyl) phenyl) -2 (5H) -furanone, for the treatment of an inflammatory disease responsive to treatment with a non-steroidal anti-inflammatory drug. 4. Use according to claim 1 Wherein the unit dosage form comprises 12.5 mg of 3-phenyl-4- (4- (methylsulfonyl) phenyl) -2 (5H) -furanone. 5. Use according to claim 1 The method of claim 3, wherein the unit dosage form comprises 25 mg of 3-phenyl-4- (4-methylsulfonyl) phenyl) -2 (5H) -furanone. 6. Use according to claim 1 The method of claim 3, wherein the unit dosage form comprises 50 mg of 3-phenyl-4- (4- (methylsulfonyl) phenyl) -2 (5H) -furanone. 7. Use according to claim 1 3 or 4, 5 or 6 wherein the unit dosage form comprises 5 mg, 10 mg, 12.5 mg or 25 mg of 3-phenyl-4- (4- (methylsulfonyl) phenyl) -2 (5H) -furanone and the disease is non-chronic headache, pain, or swelling. 8. Use according to claim 1 The method of claim 7, wherein the disease is pain following surgery and dental procedures. Use according to claim 1 3. The disease is osteoarthritis as 3 or 4 or 5 or 6 wherein the disease is osteoarthritis. 188 649 Use according to claim 1 3 or 4, <bbo5 or 6, wherein the disease is remnatoid arthritis. The invention relates to pharmaceutical compositions for the treatment of coklbbkiyzen3za-2 mediated diseases containing 3-phenylb-4- (4- (methylsulfbnylb) phenylb) -2 (5H) furanone, and the use of theso compound in the manufacture of a medicament. The pharmaceutical composition according to the invention for the treatment of diseases mediated by cyclbxyzenase-2 containing the above compound is suitable for once-a-day administration, has a high potency in inhibiting cyclbxyzenase-2, has a long duration and a high degree of specificity due to the preferential inhibition of cyclbxyzenase3. 2 compared with cyclooxyzenase-1. 3-Phenylb-4- (4- (methylsulfbnylb) phenylb) - (5H) -furanbn-2 is represented by the following structural formula. Non-steroidal anti-inflammatory drugs are given 2 to 4 times daily. The relatively short lifetime of most NSAIDs makes once daily administration practically unrealistic, and even twice daily administration is very rare. Relatively large doses wiped out for treatment with known unstable anti-inflammatory drugs by administering them once a day would cause severe side effects, so there is a general perception that once-a-day administration is impossible to achieve. Surprisingly, a compound has been identified that can be administered once a day and has no unacceptable side effects under this regimen, and in particular, the compound will not cause unacceptable side effects on the digestive system. In U.S. Patent No. 5,474,995 issued on 12 rdings 1995, in the publication of the patent application for intramedullarynus, WO 95/00501 of January 5, 1995, and the publication of patent application for mousson-bdbwet, WO 95/18799 of July 13, 1995, 3,4-bsubstitial furanones and their derivatives as potent, selective cyclbxosene-2 inhibitors, including 3-phenylb-4- (4- (methylsulfbnylb) phenylb) -2 (5H) -: furanbn, utility and production methods. As reported in U.S. Patent No. 5,474,995, the compounds disclosed therein, including 3-phenylb-4- (4- (methylsulfbnylb) -phenylb) -2 (5H) -fur3nbn, are useful for pain relief, lowering fever and combating inflammation in many disease states, including acute articular bones, symptoms of z-opo or other viral infections, colds, low back pain, neck pain, dysmenorrhea, anger pain, toothache, joint injuries and strain injuries, myositis , neuralgia, synovitis, arthritis, including rheumatoid arthritis, decongestant joint diseases (osteoarthritis), gout and ankylosing spondylitis, bursitis, burns, injuries after surgery and dental surgery. Moreover, such a compound can inhibit cellular neoplastic transformations and the growth of metastatic disease, and thus can be used in the treatment of cancer. It is also suitable for the treatment of dementia including pre-senile dementia and senile dementia and in particular dementia related to Alzheimer's disease (Alzheimer's type dementia). 188 649 This compound will also inhibit prostanoid-induced smooth muscle contraction by preventing the synthesis of contractile prostanoids, and can therefore be used in the treatment of dysmenorrhea, premature labor and asthma. Due to the potent inhibitory properties of cyclooxygenase-2 (COX-2) and / or the selectivity of inhibition of COX-2 over cyclooxygenase-1 (COX-1), this particular compound also finds use as an alternative to known non-steroidal anti-inflammatory drugs (NSAIDs), especially in cases where these NSAIDs may be contraindicated, e.g. in patients with gastric ulcer, gastritis, local enteritis, ulcerative colitis, diverticulitis, or recurrent digestive disorders, gastrointestinal bleeding, coagulation disorders such as hypoprothrombinemia, haemophilia, or other bleeding problems (including those associated with reduced or impaired platelet function), in patients with kidney problems (e.g. impaired kidney function), in patients waiting for surgery in surgery or treated with anticoagulants, and in patients who react with asthma to NSAIDs al. For the treatment of each of these cyclooxygenase-2 related diseases, the compound can be administered orally. We have found that 3-phenyl-4- (4- (methylsulfonyl) phenyl) -2 (5H) -furanone has a surprising combination of properties that makes it possible to prepare and use unexpectedly a composition containing this compound. Not only is this compound potent, safe and effective at low oral doses of 12.5 mg, 25 mg and 50 mg per day, it also has a half-life in humans long enough for single oral doses as above given once daily to provide effective and safe anti-inflammatory treatment throughout the 24-hour period. It is especially useful in treating chronic diseases including arthritis, pain, Alzheimer's disease, and the like.